The Ohio State University Dream Team: Innovation for Well-being fellowship and coaching program.

Background: Nearly 70% of faculty experience very high levels of stress. Integrative Nurse Coaching (INC) can help by assisting clients in establishing goals and embarking on new lifestyle behaviors that help to decrease perceived stress, achieve work life integration, and enhance life satisfaction. Our goal was to evaluate a faculty coaching and fellowship program to support faculty well-being while developing innovation competency. Methods: We employed an INC paradigm to coach five faculty to build confidence and competence in innovation and enhance well-being. We offered monthly group and individual coaching and used a qualitative research thematic analysis to determine themes important for the fellow and group experiences, identify outcomes, and create recommendations for the future. Results: We identified the following themes as outcomes for our program: (1) enhanced connection, comradery, and support; (2) increased confidence and competence in navigating academia; (3) shift from a fixed mindset to an innovation mindset; and (4) increased ability to identify and manage stress and burnout. Fellows also experienced a shift from focusing on individual needs to addressing the needs of the community at the college. Conclusion: Nurse coaching is an effective strategy to address faculty stress and burnout. Additional research is needed to evaluate the Innovation for Well-being faculty fellowship program and its impact on the academic community.

Use of deep artificial neural networks to identify stroke during triage via subtle changes in circulating cell counts.

BACKGROUND: The development of tools that could help emergency department clinicians recognize stroke during triage could reduce treatment delays and improve patient outcomes. Growing evidence suggests that stroke is associated with several changes in circulating cell counts. The aim of this study was to determine whether machine-learning can be used to identify stroke in the emergency department using data available from a routine complete blood count with differential. METHODS: Red blood cell, platelet, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were assessed in admission blood samples collected from 160 stroke patients and 116 stroke mimics recruited from three geographically distinct clinical sites, and an ensemble artificial neural network model was developed and tested for its ability to discriminate between groups. RESULTS: Several modest but statistically significant differences were observed in cell counts between stroke patients and stroke mimics. The counts of no single cell population alone were adequate to discriminate between groups with high levels of accuracy; however, combined classification using the neural network model resulted in a dramatic and statistically significant improvement in diagnostic performance according to receiver-operating characteristic analysis. Furthermore, the neural network model displayed superior performance as a triage decision making tool compared to symptom-based tools such as the Cincinnati Prehospital Stroke Scale (CPSS) and the National Institutes of Health Stroke Scale (NIHSS) when assessed using decision curve analysis. CONCLUSIONS: Our results suggest that algorithmic analysis of commonly collected hematology data using machine-learning could potentially be used to help emergency department clinicians make better-informed triage decisions in situations where advanced imaging techniques or neurological expertise are not immediately available, or even to electronically flag patients in which stroke should be considered as a diagnosis as part of an automated stroke alert system.

A Holistic Transcendental Leadership Model for Enhancing Innovation, Creativity and Well-Being in Health Care.

Burnout in health care employees and leaders is at an all-time high. Strategies to address burnout can fall short of addressing the broad range of underlying causes, including both organizational culture and personal factors. The National Academies of Medicine has set forth recommendations to address health care burnout from a leadership-based systems level that focuses on the whole employee, body, mind, and spirit. Across generations and societies, there is a growing trend toward spirituality and meaning as a critical component of both personal life and work. Among the working-age millennials, values of purpose and greater societal good take precedent and impact work choices and behaviors. Spiritually based values such as a sense of purpose, the transcendence of the self and ego, and the acknowledgment of something greater than our collective selves, are present in both popular culture and research on transcendental models of leadership. This article presents a model of holistic transcendental leadership that can be leveraged in the health care workplace to enhance innovation and creativity, while placing a novel emphasis on the physical, emotional, and spiritual well-being at the individual, group, and organizational level.

A blueprint for nursing innovation centers.

BACKGROUND: The interest in and demand for healthcare innovation has heightened amid the COVID-19 pandemic. Organizations are challenged to balance the goals of daily operations with innovation to stay relevant and compete in the marketplace. Innovation is critical for not only the success and sustainability of organizations, but the well-being of the faculty, staff, and clients they serve. PURPOSE: In this article, we present an overview of several Nursing Innovation Centers in the United States as well as examples of colleges without formal innovation centers but who are addressing innovation in their programs. METHODS: We examined the subjective experience of nursing innovation in seven colleges of nursing using semi-structured intervieweds and thematic analysis. FINDINGS: We discuss four themes for creating an innovation center or innovation focus and six themes important for sustainability and impact. In addition, we provide a working model for these themes and provide lessons learned along with trends and recommendations for the future. DISCUSSION: This information provides guidance and a framework for academic and practice organizations aspiring to create opportunities for innovation to flourish in their institutions. We also encourage leadership to critically evaluate and address biases in faculty hiring, research evaluation, publication practices, educational opportunities and mentoring to overcome the diversity innovation paradox.

High-Throughput Profiling of Circulating Antibody Signatures for Stroke Diagnosis Using Small Volumes of Whole Blood.

Accurate stroke recognition during triage can streamline care and afford patients earlier access to life-saving interventions. However, the tools currently available to clinicians for prehospital and early in-hospital identification of stroke are limited. The peripheral immune system is intricately involved in stroke pathology and thus may be targetable for the development of immunodiagnostics. In this preliminary study, we sought to determine whether the circulating antibody pool is altered early in stroke, and whether such alterations could be leveraged for diagnosis. One hundred microliters of peripheral whole blood was sampled from 19 ischemic stroke patients, 17 hemorrhagic stroke patients, and 20 stroke mimics in the acute phase of care. A custom-fabricated high-density peptide array comprising 125,000 unique probes was used to assess the binding characteristics of blood-borne antibodies, and a random forest-based approach was used to select a parsimonious set of probes with an optimal ability to discriminate between groups. The coordinate antibody binding intensities of the top 17 probes identified in our analysis displayed an ability to differentiate the total pool of stroke patients from stroke mimics with 92% sensitivity and 90% specificity, as well as detect hemorrhage with 88% sensitivity and 87% specificity, as determined using a same-set cross-validation. These preliminary findings suggest that stroke-associated alterations in the circulating antibody pool may have clinical utility for diagnosis during triage, and that such a possibility warrants further investigation.

Shifts in Leukocyte Counts Drive the Differential Expression of Transcriptional Stroke Biomarkers in Whole Blood.

Our group recently identified a panel of ten genes whose RNA expression levels in whole blood have utility for detection of stroke. The purpose of this study was to determine the mechanisms by which these genes become differentially expressed during stroke pathology. First, we assessed the transcriptional distribution of the ten genes across the peripheral immune system by measuring their expression levels on isolated neutrophils, monocytes, B-lymphocytes, CD-4+ T-lymphocytes, CD-8+ T-lymphocytes, and NK-cells generated from the blood of healthy donors (n = 3). Then, we examined the relationship between the whole-blood expression levels of the ten genes and white blood cell counts in a cohort of acute ischemic stroke patients (n = 36) and acute stroke mimics (n = 15) recruited at emergency department admission. All ten genes displayed strong patterns of lineage-specific expression in our analysis of isolated leukocytes, and their whole-blood expression levels were correlated with white blood cell differential across the total patient population, suggesting that many of them are likely differentially expressed in whole blood during stroke as an artifact of stroke-induced shifts in leukocyte counts. Specifically, factor analysis inferred that over 50% of the collective variance in their whole-blood expression levels across the patient population was driven by underlying variance in white blood cell counts alone. However, the cumulative expression levels of the ten genes displayed a superior ability to discriminate between stroke patients and stroke mimics relative to white blood cell differential, suggesting that additional less prominent factors influence their expression levels which add to their diagnostic utility. These findings not only provide insight regarding this particular panel of ten genes, but also into the results of prior stroke transcriptomics studies performed in whole blood.

High-throughput profiling of the circulating proteome suggests sexually dimorphic corticosteroid signaling following ischemic stroke.

Increasing evidence suggests that there are innate differences between sexes with respect to stroke pathophysiology; however, the molecular mechanisms underlying these differences remain unclear. In this investigation, we employed a shotgun approach to broadly profile sex-associated differences in the plasma proteomes of a small group of male ( n = 6) and female ( n = 4) ischemic stroke patients. Peripheral blood was sampled during the acute phase of care, and liquid chromatography electrospray ionization mass spectrometry was used to quantify plasma proteins. We observed widespread differences in plasma composition, as 77 out of 294 detected proteins were significantly differentially expressed between sexes. Corticosteroid-binding globulin (CBG), a negative acute-phase reactant that inversely regulates levels of bioactive free cortisol, was the most dramatically differentially regulated, exhibiting 16-fold higher abundance in plasma from women relative to men. Furthermore, functional annotation analysis revealed that the remaining differentially expressed proteins were significantly enriched for those involved in response to corticosteroid signaling. Plasma CBG levels were further examined in an additional group of male ( n = 19) and female ( n = 28) ischemic stroke patients, as well as a group of male ( n = 13) and female ( n = 18) neurologically normal controls. CBG levels were significantly reduced in male stroke patients relative to male controls; however, no differences were observed between female stroke patients and female controls, suggesting that women may exhibit an attenuated cortisol response to stroke. Collectively, our findings reinforce the idea that there are sex-associated differences in stroke pathophysiology and suggest that cortisol signaling should be investigated further as a potential molecular mediator.

Nursing genetics and genomics: The International Society of Nurses in Genetics (ISONG) survey.

BACKGROUND: The International Society of Nursing in Genetics (ISONG) fosters scientific and professional development in the discovery, interpretation, and application of genomic information in nursing research, education, and clinical practice. OBJECTIVES: Assess genomic-related activities of ISONG members in research, education and practice, and competencies to serve as global leaders in genomics. DESIGN: Cross-sectional survey (21-items) assessing genomic-related training, knowledge, and practice. SETTINGS: An email invitation included a link to the anonymous online survey. PARTICIPANTS: All ISONG members (n = 350 globally) were invited to partake. METHODS: Descriptive statistics and Wilcoxon Rank Sum Test for between-group comparisons. RESULTS: Respondents (n = 231, 66%), were mostly Caucasian, female, with a master's degree or higher. Approximately 70% wanted to incorporate genomics in research, teaching, and practice. More than half reported high genomic competency, and over 95% reported that genomics is relevant the next 5 years. CONCLUSIONS: Findings provide a foundation for developing additional educational programs for an international nursing workforce in genomics.

Leukocyte Dynamics Influence Reference Gene Stability in Whole Blood: Data-Driven qRT-PCR Normalization Is a Robust Alternative for Measurement of Transcriptional Biomarkers.

BACKGROUND: The use of reference genes for normalization of whole blood qRT-PCR data may be problematic in conditions such as stroke which induce alterations in white blood cell differential. In this study, we assessed the influence of stroke on the stability of commonly employed reference genes, and we evaluated data-driven normalization as an alternative. METHODS: Peripheral whole blood was sampled from 33 stroke patients and 29 controls, and qRT-PCR was used to measure the expression levels of 10 target genes whose transcripts are known stroke biomarkers. Target gene expression levels were normalized via those of 2 frequently cited reference genes (ACTB and B2M) as well as with the NORMA-Gene data-driven normalization algorithm. RESULTS: Whole blood expression levels of reference genes were significantly altered in stroke patients relative to controls. In comparison to normalization via reference genes, NORMA-Gene produced more robust target gene expression data in terms of differential expression dynamics, variance properties, and diagnostic performance. CONCLUSIONS: Our findings suggest that whole blood expression levels of commonly used reference genes may be sensitive to changes in white blood cell differential, and that data-driven qRT-PCR normalization approaches offer a powerful alternative.

High Interspecimen Variability in Nucleic Acid Extraction Efficiency Necessitates the Use of Spike-In Control for Accurate qPCR-based Measurement of Plasma Cell-Free DNA Levels.

OBJECTIVE: To assess the interspecimen variability associated with plasma DNA extraction in order to provide insight regarding the necessity to use an exogenous spike-in control when measuring cell-free DNA (cfDNA) levels using quantitative polymerase chain reaction (qPCR). METHODS: Plasma specimens were obtained from 8 healthy individuals, 20 patients with cardiovascular disease risk factors, and 54 patients diagnosed with acute stroke. Specimens were spiked with an exogenous oligonucleotide fragment, and total DNA was extracted via automated solid phase anion exchange. We determined recovery of the exogenous fragment via qPCR and used this information to calculate DNA extraction efficiency. RESULTS: Plasma DNA extraction efficiencies varied dramatically between specimens, ranging from 22.9% to 88.1%, with a coefficient of variance of 28.9%. No significant differences in DNA extraction efficiencies were observed between patient populations. CONCLUSIONS: We strongly recommend the use of an exogenous spike-in control to account for variance in plasma DNA extraction efficiency when assessing cell free DNA (cfDNA) levels by qPCR in future biomarker investigations.

Monocyte-lymphocyte cross-communication via soluble CD163 directly links innate immune system activation and adaptive immune system suppression following ischemic stroke.

CD163 is a scavenger receptor expressed on innate immune cell populations which can be shed from the plasma membrane via the metalloprotease ADAM17 to generate a soluble peptide with lympho-inhibitory properties. The purpose of this study was to investigate CD163 as a possible effector of stroke-induced adaptive immune system suppression. Liquid biopsies were collected from ischemic stroke patients (n = 39), neurologically asymptomatic controls (n = 20), and stroke mimics (n = 20) within 24 hours of symptom onset. Peripheral blood ADAM17 activity and soluble CD163 levels were elevated in stroke patients relative to non-stroke control groups, and negatively associated with post-stroke lymphocyte counts. Subsequent in vitro experiments suggested that this stroke-induced elevation in circulating soluble CD163 likely originates from activated monocytic cells, as serum from stroke patients stimulated ADAM17-dependant CD163 shedding from healthy donor-derived monocytes. Additional in vitro experiments demonstrated that stroke-induced elevations in circulating soluble CD163 can elicit direct suppressive effects on the adaptive immune system, as serum from stroke patients inhibited the proliferation of healthy donor-derived lymphocytes, an effect which was attenuated following serum CD163 depletion. Collectively, these observations provide novel evidence that the innate immune system employs protective mechanisms aimed at mitigating the risk of post-stroke autoimmune complications driven by adaptive immune system overactivation, and that CD163 is key mediator of this phenomenon.

Stroke-associated pattern of gene expression previously identified by machine-learning is diagnostically robust in an independent patient population.

Our group recently employed genome-wide transcriptional profiling in tandem with machine-learning based analysis to identify a ten-gene pattern of differential expression in peripheral blood which may have utility for detection of stroke. The objective of this study was to assess the diagnostic capacity and temporal stability of this stroke-associated transcriptional signature in an independent patient population. Publicly available whole blood microarray data generated from 23 ischemic stroke patients at 3, 5, and 24 h post-symptom onset, as well from 23 cardiovascular disease controls, were obtained via the National Center for Biotechnology Information Gene Expression Omnibus. Expression levels of the ten candidate genes (ANTXR2, STK3, PDK4, CD163, MAL, GRAP, ID3, CTSZ, KIF1B, and PLXDC2) were extracted, compared between groups, and evaluated for their discriminatory ability at each time point. We observed a largely identical pattern of differential expression between stroke patients and controls across the ten candidate genes as reported in our prior work. Furthermore, the coordinate expression levels of the ten candidate genes were able to discriminate between stroke patients and controls with levels of sensitivity and specificity upwards of 90% across all three time points. These findings confirm the diagnostic robustness of the previously identified pattern of differential expression in an independent patient population, and further suggest that it is temporally stable over the first 24 h of stroke pathology.

Circulating leucocytes perpetuate stroke-induced aortic dysfunction.

NEW FINDINGS: What is the central question of this study? Does a stroke event influence aortic endothelial function; and what is the role of peripheral circulating leucocytes in stroke on the vascular reactivity of the aorta? What is the main finding and its importance? In vitro co-culture experiments demonstrated that aortic endothelium-dependent relaxation was impaired when rat aortic rings were co-cultured with leucocytes stimulated with serum from stroke patients. Impaired vascular reactivity was not observed in aortic rings without leucocytes stimulated with serum from stroke patients or age-matched control patients with or without leucocytes. These data suggest that leucocyte-dependent altered aortic endothelium-dependent relaxation with stroke and the systemic consequences of stroke on vascular inflammation may occur in the aorta. Post-stroke inflammation has been linked to poor stroke outcomes. The vascular endothelium senses and responds to circulating factors, in particular inflammatory cytokines. Although stroke-associated local cerebrovascular dysfunction is well reported, the effects of a stroke on conduit artery function are not fully understood. We tested the hypothesis that serum from stroke patients triggers leucocyte-dependent aortic endothelial dysfunction that is associated with elevated concentrations of cytokines. Total leucocytes were isolated from healthy individuals, and the cells were incubated in serum from control subjects or stroke patients for 6 h. The quantity of cytokines in media was determined using an immunoassay. Vascular reactivity was determined by the rat aortic rings that were co-cultured with or without leucocytes and stimulated with serum samples from control subjects or stroke patients. Endothelium-dependent dilatation was significantly impaired in aortic rings co-cultured with leucocytes plus serum from stroke patients (50 ± 30 versus 85 ± 13%, P < 0.05) versus serum from control subjects. In contrast, no difference was observed in aortic function stimulated with serum from control subjects or stroke patients without total leucocytes. Likewise, total leucocyte-derived cytokine concentrations were significantly increased in a time-dependent manner on stimulation with serum from stroke patients (P < 0.05). These observations support the concept that the increased response of leucocytes drives the development of stroke-associated vascular endothelial dysfunction. As such, pharmacologically targeting the source of inflammatory cytokines might alleviate stroke-associated peripheral vascular dysfunction.

Circulating extracellular DNA levels are acutely elevated in ischaemic stroke and associated with innate immune system activation.

OBJECTIVE: The objective of this work was to assess the ability of peripheral blood cell-free DNA (cfDNA) levels to identify ischaemic stroke early in the acute phase of care, as well as to examine the relationship between peripheral blood cfDNA levels and stroke-induced innate immune system activation. METHODS: Upon emergency department admission, peripheral blood samples were obtained from 43 patients experiencing acute ischaemic stroke and 20 patients identified as stroke mimics. Plasma cfDNA levels were measured using quantitative polymerase chain reaction (qPCR), infarct volume and NIH stroke scale (NIHSS) were used to assess injury severity, and peripheral blood neutrophil count was used as a measure of innate immune system status. RESULTS: Peripheral blood cfDNA levels were significantly elevated in patients suffering stroke relative to those diagnosed as stroke mimics, and could differentiate between groups with 86% (95% CI = 72-95%) sensitivity and 75% (95% CI = 51-91%) specificity. Furthermore, cfDNA levels displayed significant positive associations between both infarct volume and peripheral blood neutrophil count within the stroke group. CONCLUSIONS: These findings suggest that assessment of peripheral blood cfDNA levels may be useful for the identification of ischaemic stroke in the acute care setting, and provide associative evidence that cfDNA is a potential activator of the peripheral innate immune system in response to cerebral ischaemia.

Peripheral blood AKAP7 expression as an early marker for lymphocyte-mediated post-stroke blood brain barrier disruption.

Our group recently identified 16 genes whose peripheral blood expression levels are differentially regulated in acute ischemic stroke. The purpose of this study was to determine whether the early expression levels of any of these 16 genes are predictive for post-stroke blood brain barrier (BBB) disruption. Transcriptional expression levels of candidate genes were measured in peripheral blood sampled from ischemic stroke patients at emergency department admission, and BBB permeability was assessed at 24 hour follow up via perfusion-weighted imaging. Early heightened expression levels of AKAP7, a gene encoding a protein kinase A-binding scaffolding molecule, were significantly associated with BBB disruption 24 hours post-hospital admission. We then determined that AKAP7 is predominantly expressed by lymphocytes in peripheral blood, and strongly co-expressed with ITGA3, a gene encoding the adhesion molecule integrin alpha 3. Subsequent in vitro experiments revealed that heightened expression of AKAP7 and ITGA3 in primary human lymphocytes is associated with a highly adherent phenotype. Collectively, our results suggest that AKAP7 expression levels may have clinical utility as a prognostic biomarker for post-stroke BBB complications, and are likely elevated early in patients who later develop post-stroke BBB disruption due to the presence of an invasive lymphocyte population in the peripheral blood.

Immune biomarkers for the diagnosis of mild traumatic brain injury.

BACKGROUND: In 2010, there were approximately 2.2 million emergency room visits associated with traumatic brain injury (TBI), with 80 percent diagnosed as mild TBI or concussion. In addition, there are a large number of TBIs, especially mild TBIs, which go either unreported by patients or initially undiagnosed by clinicians. Our team has previously identified a panel of immune-related genes that can diagnose ischemic stroke at triage, and due to shared pathophysiological mechanisms of TBI and stroke, we hypothesized that this panel of genes may also be utilized for the diagnosis of TBI. OBJECTIVES: The primary aims of this pilot study were to: (1) characterize changes in a panel of immune-related genes in TBI; (2) identify immune-related biomarkers that may be used to diagnose TBI and (3) describe the peripheral immune response following TBI. METHODS: Blood was drawn from TBI patients no later than 24 h of injury onset and matched control subjects. Real-time PCR was used to measure gene expression, and a white blood cell differential was performed to obtain neutrophil and lymphocyte percentages. RESULTS: Relative mRNA expression of ARG1, LY96, MMP9, s100a12 was significantly increased and CCR7 was significantly decreased in peripheral blood of TBI patients within 24 hours of injury compared to control subjects. We also observed a different pattern of leukocyte dynamics following TBI between mild and severe TBI. CONCLUSIONS: We have described a panel of immune-related genes that can accurately predict/diagnose TBI with higher sensitivity and specificity of other biomarkers to date.

Rethinking Recovery: Incorporating Holistic Nursing Perspectives in Poststroke Care.

Stroke is a life-changing experience. Current treatments focus on treating the condition, rather than the whole person. The goal of this report was to communicate the benefits of a holistic approach to the treatment and recovery of stroke. Our intent was to begin a conversation to transform our approach to stroke care to focus on the whole person, body, mind, and spirit. Wellness approaches are fiscally responsible ways of providing holistic care for patients and their family members to help them achieve optimal individualized recovery. Very few multidimensional programs for wellness exist for patients with stroke and brain injury. Given the changes in health care and the Call to Action set forth in the Institute of Medicine's 2010 report, it would behoove us to consider holistic approaches to stroke care and research programs. Nurses are uniquely positioned to implement multidisciplinary, innovative holistic approaches to address solutions for issues in stroke care. Wellness is a critically important area of stroke care and an opportunity for research. As advocates for patients, and nurses with personal experiences, we hope this commentary stimulates conversation around developing and testing multidimensional holistic programs of wellness for stroke prevention, treatment, and recovery.

Understanding Genomic Knowledge in Rural Appalachia: The West Virginia Genome Community Project.

PURPOSE: Rural communities have limited knowledge about genetics and genomics and are also underrepresented in genomic education initiatives. The purpose of this project was to assess genomic and epigenetic knowledge and beliefs in rural West Virginia. SAMPLE: A total of 93 participants from three communities participated in focus groups and 68 participants completed a demographic survey. The age of the respondents ranged from 21 to 81 years. Most respondents had a household income of less than $40,000, were female and most were married, completed at least a HS/GED or some college education working either part-time or full-time. METHOD: A Community Based Participatory Research process with focus groups and demographic questionnaires was used. FINDINGS: Most participants had a basic understanding of genetics and epigenetics, but not genomics. Participants reported not knowing much of their family history and that their elders did not discuss such information. If the conversations occurred, it was only during times of crisis or an illness event. Mental health and substance abuse are topics that are not discussed with family in this rural population. CONCLUSIONS: Most of the efforts surrounding genetic/genomic understanding have focused on urban populations. This project is the first of its kind in West Virginia and has begun to lay the much needed infrastructure for developing educational initiatives and extending genomic research projects into our rural Appalachian communities. By empowering the public with education, regarding the influential role genetics, genomics, and epigenetics have on their health, we can begin to tackle the complex task of initiating behavior changes that will promote the health and well-being of individuals, families and communities.

Gene expression profiling in stroke: relevance of blood-brain interaction.

Biomarker profiling is utilized to identify diagnostic and prognostic candidates for stroke. Clinical and preclinical biomarker data suggest altered circulating immune responses may illuminate the mechanisms of stroke recovery. However, the relationship between peripheral blood biomarker profile(s) and brain profiles following stroke remains elusive. Data show that neutrophil lymphocyte ratio (NLR) predicts stroke outcome. Neutrophils release Arginase 1 (ARG1) resulting in T lymphocyte suppression in peripheral blood. Interestingly, the cellular response to stroke may have implications for known biomarker profiles. Conversely, preclinical evidence suggests that upregulation of ARG1 in microglia is a marker of M2 macrophages and may influence neuroprotection. Comparing clinical and preclinical studies creates opportunities to explore the molecular mechanisms of blood and brain biomarker interactions in stroke.